Sample collection from asteroid (162173) Ryugu by Hayabusa2: Implications for surface evolution.

The near-Earth asteroid (162173) Ryugu is thought to be a primitive carbonaceous object that contains hydrated minerals and organic molecules. We report sample collection from Ryugu's surface by the Hayabusa2 spacecraft on 21 February 2019. Touchdown images and global observations of surface colors are used to investigate the stratigraphy of the surface around the sample location and across Ryugu. Latitudinal color variations suggest the reddening of exposed surface material by solar heating and/or space weathering. Immediately after touchdown, Hayabusa2's thrusters disturbed dark, fine grains that originate from the redder materials. The stratigraphic relationship between identified craters and the redder material indicates that surface reddening occurred over a short period of time. We suggest that Ryugu previously experienced an orbital excursion near the Sun.

Comparative antiplatelet effects of aspirin, vapiprost and GR144053, a GPIIb/IIIa antagonist, with a special reference to the role of platelet microaggregates.

Microthrombi produced have a potential to form larger thrombi, leading to vascular occlusions. Recently, a new device to easily detect microaggregates using laser-light scattering (LS) has been developed. We adopted this device to comparatively evaluate the inhibitory effects of aspirin (1,3 or 10 mg kg(-1)), vapiprost (0.3, 1 or 3 mg kg(-1)) or GR144053 (0.1, 0.3 or 1 mg kg(-1)) on ex vivo aggregation of hamster platelets in relation to their in vivo antithrombotic effects. A transluminal thrombus was produced in the hamster femoral artery by the photochemical reaction. Each compound was injected i.v. as a bolus 10 min prior to the reaction, showing a dose-dependent antithrombotic effect, i.e. they prolonged the time before the artery occluded. At that time cyclic flow reductions occurred more marked when aspirin or vapiprost was given. At the end of experiments, blood was collected to evaluate the platelet aggregation using both the new LS device and the conventional optical density (OD) method. Many more small aggregates were still formed when the highest dose of aspirin or vapiprost was used as compared with that of GR144053, although suppression of the platelet aggregation using the OD method, prolongation of the occlusion time and the bleeding time were quite similar. In conclusion, a GPIIb/IIIa antagonist markedly suppressed the microthrombi and reduced the cyclic flow reduction. This further indicates the importance of small aggregates as triggers of thrombosis and shows that prevention of their formation may result in improved vascular patency after thrombotic insult.

Synthesis of carbapenam skeletons using a ruthenium-catalyzed cyclization.

Carbapenam is a very important skeleton of beta-lactam antibiotics, and it has a highly strained structure. When enynes 9 were treated with RuH(2)CO(PPh(3))(3) (10 mol %) in toluene upon heating, carbapenams 10 were obtained in good yields.

Phase I study of Y-20811, a new long-acting thromboxane synthetase inhibitor by intravenous administration.

The safety, pharmacological action and pharmacokinetics of Y-20811, a thromboxane (TX) synthetase inhibitor, were investigated by single intravenous administration of 5, 10, and 25 mg each to six healthy adult male volunteers. Throughout the entire test period, no abnormality attributable to the test drug was found in subjective and objective symptoms, routine laboratory tests, physical tests, or bleeding time; and the drug was well tolerated by subjects. Inhibition of serum TXB2 production and an increase in 6-keto-prostaglandin (PG) F1 alpha production during whole-blood coagulation exhibited a dose-dependent change from 0.5 hours after administration. In addition, arachidonic acid (AA)-induced platelet aggregation was inhibited, and adenosine diphosphate (ADP)-induced secondary aggregation was also inhibited. The duration of these actions was long; inhibition of serum TXB2 production and the increase in 6-keto-PGF1 alpha production lasted for 168 hours after administration , and inhibition of platelet aggregation lasted for more than 48 h after administration. The initial phase half-life (t1/2 alpha) and final phase half-life (t1/2 beta) of Y-20811, calculated from the change in plasma concentration, were 0.1-0.3 hours and 1.9-3.1 hours, respectively. The area under the plasma concentration-time curve (AUC) increased in a dose-dependent manner, but the values of volume of distribution (Vss) and total clearance (CLt) were almost constant in any dose group. At each of the three doses, 60-64% of the dose was excreted in unchanged form, and 8-10% in conjugated form in the urine, within 48 hours after administration.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics and safety of a novel recombinant soluble human thrombomodulin, ART-123, in healthy male volunteers.

The safety and pharmacokinetics of a novel recombinant soluble human thrombomodulin, ART-123 were evaluated in single- and multiple-dose studies involving 16 healthy male volunteers. ART-123 was administered by intravenous infusion over 2 hours. The single-dose study indicated that plasma ART-123 levels at doses of 0.03, 0.1, and 0.3 mg declined biexponentially and those half-lives were approximately 4 hours (t1/2 alpha) and 20 hours (t1/2 beta), respectively. The mean plasma peak concentration and area under the plasma concentration-time curves increased in proportion to the given doses. Mean urinary recovery within the first 48 hours was between 54.3% and 59.8% of dose. In the multiple-dose study, ART-123 was administered at a dose of 0.2 mg once daily for 3 days. ART-123 did not accumulate as judged from plasma concentrations and urinary recovery. There were no abnormal findings in objective symptoms and laboratory findings, including blood pressure, heart rate, electrocardiogram, body temperature, hematology, bleeding time, coagulation and hemostatic parameters, blood chemistry, and urinalysis. There were no significant adverse reactions or abnormalities in physical and laboratory examinations that could definitely be attributed to the drug at a dose of 0.3 mg as a single administration and at a dose of 0.2 mg once daily for 3 days. These results indicate that ART-123 is safe at doses up to 0.2 mg once daily for 3 days and may have clinical application. Further studies are needed, however, to evaluate the safety and pharmacokinetics of ART-123 in the targeted population.

Phase I study of cefixime, a new oral cephalosporin.

The tolerance to and pharmacokinetics of cefixime, a new oral cephalosporin, were evaluated in healthy volunteers given the drug in single doses of 50, 100 and 200 mg and repeated doses of 200 mg bid for 14 days. In the repeated-dose study, there were mild and transient subjective symptoms such as soft stools, diarrhea, and anorexia, which disappeared without additional treatment during the dosing period. Slight increases in eosinophil and serum amylase levels were also observed. The serum concentrations of cefixime peaked at 0.71, 1.17, and 2.08 micrograms/mL on average, four to five hours after dosing with 50, 100, and 200 mg, respectively, and the half-lives were 2.54, 2.38, and 2.29 hours. Serum concentrations and urinary recoveries after dosing with 100 mg were little affected by food ingestion. There was no evidence of cefixime accumulation in the body by repeated dosing since mean serum concentrations and urinary recoveries were almost the same on the first, third, seventh, and 14th days of dosing.

Phase I study of Y-20811, a new long-acting thromboxane synthetase inhibitor by oral administration.

The safety, pharmacological action and pharmacokinetics of the thromboxane (TX) synthetase inhibitor Y-20811, a prospective medication for ischemic vascular disorder, were investigated in Phase I clinical trials in which single and repeated doses were administered orally to 32 healthy adult male volunteers. In the single-dose study, subjects were given single doses of 2.5, 5, 10, 25, 50, and 100 mg; in the repeated-dose study, a single dose of 50 mg was administered daily for 5 days. In the repeated-dose study, slight elevation of liver function test parameters in 1 subject was observed, but throughout the trials, no abnormality attributable to the test drug was found in other routine laboratory tests, subjective and objective findings, vital signs (blood pressure, pulse rate, body temperature, respiration rate), ECG, or bleeding time; nor did any finding indicate a problem concerning the safety of Y-20811. In both single- and repeated-dose studies, inhibition of the serum TXB2 production and an increase in the 6-keto-prostaglandin F1 alpha production during whole-blood coagulation, and inhibition of arachidonic acid-induced platelet aggregation were observed from 1 hour after administration of Y-20811. The duration of these actions was long, the former two lasting 168 hours (1 week) and the latter 48-72 hours or more. Slight inhibition of adenosine diphosphate-induced secondary platelet aggregation was also observed. The maximum plasma concentration time (tmax) of Y-20811 was 0.5-1.1 hours. The initial-phase half-life (t1/2 alpha) was 0.8-1.1 hours and the final-phase half-life (t1/2 beta) was 4.7-9.2 hours.(ABSTRACT TRUNCATED AT 250 WORDS)

Aldose reductase inhibitory and uricosuric activities of FK366 in healthy volunteers.

The pharmacokinetics, and aldose reductase (AR) inhibitory and uricosuric activities of FK366 were studied in healthy volunteers given a single oral dose of 150, 300, or 600 mg after fasting, 600 mg after a meal, or 300 mg twice a day for 8 days after meals. The AR inhibition was assessed by the percent reduction from the predrug dulcitol values in red blood cells converted from exogenous galactose by AR. Aldose reductase inhibition paralleled the plasma concentrations of FK366, with maximum inhibitions of 31.6, 48.0, and 56.9% at doses of 150, 300, and 600 mg, respectively. With multiple dosing, the inhibition scarcely differed between the first (41.8%) and last doses (41.5%). Serum uric acid decreased dose dependently, with a minimum concentration of 4.0 mg/dL (predrug: 5.5 mg/dL) 8 hours after receiving 600 mg. With multiple dosing, serum uric acid levels declined rapidly and remained at a concentration of 3.1 mg/dL beginning at day 3. Urinary excretion of uric acid was high on day 1 (879 mg/day), but decreased significantly to 654 mg/day on day 2 and then stabilized. The pharmacokinetics of FK366 were linear over the dose range studied, with an elimination half-life of 8.2 hours and urinary recovery of 27.2% as unchanged drug. FK366 was well tolerated by all subjects.

Phase I study of DQ-2556, a new parenteral 3-quaternary ammonium cephalosporin antibiotic.

The safety and pharmacokinetic properties of DQ-2556, a new parenteral cephalosporin, were evaluated using healthy volunteers after 5-minute intravenous infusion of doses of 250, 500, 1000, or 2000 mg and a 1-hour infusion of 2000 mg, and an intramuscular dose of 500 mg. The half-lives of DQ-2556 ranged from 1.64 to 2.15 hours. The peak serum concentrations and area under the curve values were linearly correlated to the doses. The mean urinary recoveries were 80.0 to 85.5% of a dose within 24 hours. Salivary concentrations of the drug were low. There was no accumulation of DQ-2556 after 9 administrations every 12 hours. DQ-2556 was well tolerated.

Autoregulation of histamine release in medulla oblongata via H3-receptors in rabbits.

The release of histamine (HA) from the rostral ventrolateral medulla (RVL), the raphe nuclei (nR), and the solitary nucleus (nTS) was investigated in anesthetized rabbits using microdialysis and high-performance liquid chromatography. HA release upon electrical stimulation of the posterior hypothalamus (PH), where histaminergic cell bodies are located, was increased to 168% of the baseline level in the RVL (n = 6), 139% of the baseline level in the nR (n = 5), and 166% of the baseline level in the nTS (n = 4). Upon perfusion of thioperamide, an H3-receptor antagonist, via a microdialysis probe, HA release from the RVL, nR and nTS increased. The increase in HA release from the RVL, nR and nTS following thioperamide perfusion was suppressed by co-perfusion of thioperamide and an H3-receptor agonist, imetit. We found that HA is released from the RVL, nR and nTS, that the HA release from all three areas is increased upon stimulation of the PH, and that the HA release is locally influenced in opposite directions by thioperamide and imetit. These results suggest that HA release in the medulla oblongata is controlled by the PH and that H3-receptors participate in the autoregulation of HA release by providing negative feedback locally. Autoregulation of HA release via H3-receptors may be important for maintaining tonic output to the sympathetic nervous system.

Central mediation of tracheal pressure through H1 and H2 receptors after histamine administration to the fourth ventricle of anesthetized rabbit.

Administration of 1.5, 5.0 and 15 nmol histamine (HA) into the fourth ventricle (IVth) decreased tracheal pressure (PT) dose-dependently in anesthetized rabbits. Maximum decrease of PT occurred 0.9 +/- 0.1 min (mean +/- S.E.M., n = 9) after administration of 15 nmol, and recovery occurred at 4.5 +/- 1.0 min (n = 9). The decrease of PT was blocked by the H1 receptor antagonist, pyrilamine administration into the IVth, or intravenous injection of the alpha-adrenoceptor antagonist, phentolamine. Recovery from the PT decrease was delayed by the H2 receptor antagonist, cimetidine. The results suggest that HA centrally decreases PT through H1 receptors, which action is mediated by the sympathetic nervous system, and this decrease may be modulated through H2 receptors.

Involvement of central histaminergic neurons in polypnea induced by hyperthermia in rabbits.

A role of central histamine in the preoptic area/anterior hypothalamus (POA/AH) for the regulation of hyperthermia-induced polypnea was examined in anesthetized, paralyzed, vagotomized and artificially ventilated rabbits. Phrenic nerve activities were recorded to monitor respiratory neuronal output. Hyperthermia increased respiratory frequency by reductions of inspiratory time (T(I)) and expiratory time (T(E)). Pyrilamine, an H1 receptor antagonist, which was applied to the POA/AH reduced polypnea under hyperthermia. The effect of S+alpha-fluoromethylhistidine, a specific inhibitor of histidine decarboxylase, applied in a lateral ventricle was comparable to the effect of pyrilamine on polypnea. Moreover, histamine dihydrochloride applied into the POA/AH at a normal body temperature produced polypnea by reductions of T(I) and T(E). The results suggest that central histamine in the POA/AH contributes to the generation of polypnea in hyperthermia through H1 receptors.

Effect of dietary fat content on oral bioavailability of menatetrenone in humans.

The purpose of this investigation was to determine the effects of fat content and frequency of meals on the oral bioavailability of menatetrenone (2-methyl-3-all-trans-tetraprenyl-1,4-naphthoquinone), a vitamin K2 with four isoprene units. In the first series of studies, menatetrenone (15 mg) was administered at breakfast time to 18 healthy male volunteers after meals with three different fat contents (meals A, B, and C) on three occasions in a crossover design. The three types of meals had almost the same calorie content (721-746 kcal) with varied fat contents (A, 8.8 g; B, 20.0 g; C, 34.9 g). The area under the plasma menatetrenone concentration-time curve within the first 24 h (AUC0-24) increased with increase of fat content: 371 +/- 194, 485 +/- 150, and 1024 +/- 341 ng.h/mL (mean +/- SD, n = 18) after meals A, B, and C, respectively. On the fourth occasion, the same dose of menatetrenone was administered to all volunteers after taking meal B, but in this case the lunch 5 h after drug administration was omitted from the protocol. The time profile of plasma menatetrenone showed a single peak when lunch was not taken, whereas it showed two peaks with lunch. On the fifth occasion, 12 out of 18 volunteers took the same dose of menatetrenone after a meal with the highest fat content (53.8 g of fat and 789 kcal; meal D), showing that AUC0-24 was almost the same as that for meal C, 1027 +/- 389 and 991 +/- 392 ng.h/mL (n = 12) for meals C and D, respectively. The oral bioavailability of lipid-soluble vitamin K was influenced by the fat content of a meal, although the increase in bioavailability seemed to reach a peak when the lipid content of the meal was > 35 g.

Gas chromatographic assay and disposition of 6-chloro-2-pyridylmethyl nitrate, a new antianginal drug, in healthy volunteers.

Quantitative determinations of plasma concentrations of 6-chloro-2-pyridylmethyl nitrate, a new antianginal drug, and its urinary metabolite, 6-chloro-2-pyridinecarboxylic acid (metabolite 1), were obtained using GC with a 63Ni electron-capture detector. 6-Chloro-2-pyridylmethyl nitrate was extracted from plasma with n-pentane. Metabolite 1 was extracted from acidic urine with ethylacetate, back extracted with 0.1 M NaHCO3, and methylated with boron trifluoride methanol reagent. The internal standard for metabolite 1 determination was prepared by propylation of metabolite 1 with boron trifluoride n-propanol reagent. The formation of the esters was confirmed by the GC-MS results. These methods proved to be sensitive and reproducible. A single dose of 6-chloro-2-pyridylmethyl nitrate (5, 10, 20, 40, or 60 mg) was given perorally to healthy volunteers. From the data, a large interindividual variability in the apparent plasma clearance was apparent (85.5 +/- 123 L/min; CV 144%). However, metabolite 1 was the main metabolite in human urine, and the interindividual variation was slight (CV 13%).

Pharmacokinetics and safety of intravenous recombinant human superoxide dismutase (NK341) in healthy subjects.

Recombinant human superoxide dismutase (rhSOD), NK341, was intravenously administered to healthy male volunteers at doses of 1750-35000 U/kg, and the safety and pharmacokinetic properties were evaluated. There were no abnormal findings attributable to the test drug throughout the study, showing that NK341 was well tolerated in healthy subjects. Tri-exponential elimination of the drug from blood was observed with half-lives of about 20 minutes (alpha phase), 80 minutes (beta phase), and 6 hours (gamma phase). The values of the maximal plasma concentration and the areas under the plasma concentration curves linearly increased with the doses given. On the other hand, the urinary recovery of the drug also increased with the dose, ranging approximately from 3%-45% of the dose. The plasma concentration of the drug measured by an enzyme immunoassay was quite comparable to SOD activity measured by electron spin resonance, suggesting that NK341 was present in blood as the active form of SOD.

Comparative pharmacokinetic and pharmacodynamic properties of oral and intravenous (+)-sotalol in healthy volunteers.

The pharmacokinetic and pharmacodynamic properties of (+)-sotalol (BMY-5763) were studied to analyse the relationship between plasma concentration and QTc prolongation in healthy male volunteers given single oral doses of 50, 100, 200 and 300 mg, repeated oral doses of 200 mg twice daily for 6.5 days, and single intravenous doses of 1.0 and 1.5 mg kg-1. The plasma concentration of (+)-sotalol peaked about 3 h after oral administration and declined with a half-life of 7.9-9.7 h. The Cmax and AUC showed dose-related increases, while the urinary recovery as the unchanged form remained constant (66-68% of the dose). During repeated oral administration the plasma concentration of (+)-sotalol reached almost a steady state on the 3rd day and there was no change in renal clearance of (+)-sotalol measured on the 1st, 4th and 7th days. After intravenous administration, (+)-sotalol in plasma decreased bi-exponentially with a terminal half-life of 7.6-8.3 h and the urinary recovery as unchanged drug amounted to 84-88% of the dose. The increase in QT interval was significant after a single oral administration except for the lowest dose, and regression analysis revealed a significant correlation between QTc interval and concentration of (+)-sotalol in plasma. The same correlation was evident with repeated oral doses on the 1st, 4th and 7th days. In the case of single intravenous administrations of (+)-sotalol, a combined pharmacokinetic-pharmacodynamic model was attempted by assuming an effect compartment.(ABSTRACT TRUNCATED AT 250 WORDS)

Multiple endocrine neoplasia type 2A.

A 40-year-old woman was admitted with complaints of headache, palpitation and diaphoresis. She had undergone right hemithyroidectomy 12 years previously. Histological reexamination of the operative specimen revealed a medullary thyroid carcinoma. Abdominal ultrasonography, CT scan and angiography showed bilateral adrenal tumors. Serum catecholamine levels in both adrenal veins were high. Based on these data, bilateral adrenalectomy was performed. Histological examination confirmed the diagnosis of pheochromocytomas. After operation, serum calcitonin and urinary noradrenaline levels were still high. Further examination by 131I-metaiodobenzylguanidine (MIBG) scintigraphy is planned.

Two cases of oral-stings by sperm bag of squid.

Two patients after eating raw squid complained of severe pain and foreign body sensation in their oral cavity. On consultation of a doctor, several small spindle-shaped stings stuck on the surface of the tongue and mucous membrane of the oral cavity were found. After all stings were pulled out, the pain was allayed and the wounds eventually healed. The foreign bodies were tentatively determined to be the sperm bag of Tadorodes pacificus. These cases suggest that fresh squids should be carefully prepared before eating them raw or "sashimi".

[IgA-lambda type myeloma complicating with autoimmune hemolytic anemia].

A 66-year-old female was admitted to our hospital with lumbago. On admission, laboratory examination revealed hemolytic anemia. Direct Coombs' test was positive, and also direct monospecific-Coombs' test by anti-C3d serum was positive. Immunoelectrophoresis showed IgA-lambda type M proteins in serum. Bone marrow aspiration disclosed increased atypical plasma cells. X-ray of skull showed punched-out lesion. From these findings, she was diagnosed as IgA (lambda) myeloma complicating with autoimmune hemolytic anemia. Hemolysis was improved by chemotherapy. It was thought that IgA and C3 were related well to hemolysis in this case.

[A case of remission induced in diffuse pleural malignant mesothelioma by the treatment with cisplatin and doxorubicin].

A 66-year-old male patient with diffuse pleural malignant mesothelioma was successfully treated with cisplatin and doxorubicin. He was admitted to our hospital because of massive pleural effusion. The diagnosis was made by pleural needle biopsy. He received 100 mg of cisplatin and 50 mg of doxorubicin every 5 weeks. Regression of the tumor and decrease of pleural effusion were observed after the treatment. A partial remission of 10 months duration was achieved. Cisplatin and doxorubicin were thought to be the most active cytotoxic agents in the treatment of malignant mesothelioma.